Rheumatoid arthritis is a serious, often crippling, disease characterized by pain and locomotor dysfunction. This sort of pain and dysfunction are among the most common and frustrating afflictions. The gravity of this disease has led to the investigation and/or adoption of a wide range of drugs for its alleviation. Aspirin has been commonly used since the turn of this century. Other major drugs used to treat arthritis include indomethacin, other salicylates, phenylbutazone, steroids, and gold. Other compounds which have been used to treat arthritis are fenoprofen, ibuprofen, naproxen, sulindac, and tolmetin.
While the known compounds can offer anti-inflammatory, antipyretic, and analgesic effects, and have proven helpful in the management of rheumatoid arthritis in many patients, when combined with other modalities such as proper rest, exercise, physical therapy, and surgery, they are less than ideal. Many of these medications exhibit serious side effects with many patients, particularly gastrointestinal damage and renal toxicity. None of these materials is universally useful in treating rheumatoid arthritis, as some patients will respond to one material while others respond favorably only to others.
Cocaine and cocaine free base have also been employed in the management of rheumatoid arthritis. Unfortunately, cocaine and cocaine free base are widely abused, and it is highly unlikely that the regulatory and drug enforcement agency issues will ever be resolved to a point that cocaine or its free base can be available on as widespread a basis as would be required for their use in the treatment of sufferers of rheumatoid arthritis.
Somers, in U.S. Pat. No. 4,512,996, disclose the use of benzoylecognine and/or benzoylnorecognine for treating rheumatoid arthritis. These compounds are formed by mammals as a metabolite of cocaine.
Horrobin, U.S. Pat. No. 4,302,447, discloses the use of gamma-linolenic acids and related materials to treat schizophrenia, obesity, menstrual disorders, skin disorders, and other conditions.
Rubin, U.S. Pat. No. 4,584,320, discloses a method for treating asthma, nasal congestion, and anaphylactic shock by administration of 8,11,14,17-eicosatetraenoic acid.
Iwamura et al., U.S. Pat. No. 4,472,432, disclose the use of a compound of the formula CH.sub.3 (CH.sub.2).sub.n CH=CHCO.sub.2 H wherein n is 10, 12, 14, or 16, for treating diabetes or improving lipid metabolism. The compounds can be separated from freshwater clams by subjecting the freshwater clams to extraction with hot water and/or an aprotic solvent.
The active ingredients in fish oil are (all-Z)-5,8,11,14,17-eicosapentaenoic acid (hereinafter EPA) and 22:6 omega3-docosahexaenoic acid (hereinafter DHA). EPA and DHA are known to be precursors in the biosynthesis of the prostaglandin PGE.sub.3.
It is disclosed in British Pat. Nos. 1,604,554 and 2,033,745 that EPA can be used to treat effectively, or to provide effective prophylaxis against, thrombo-embolic- conditions such as myocardial infarctions, strokes, or deep vein thrombosis during surgical operations. These patents disclose the extraction of EPA from fish oil such as cod liver oil or menhaden oil. The EPA may be administered by replacing butter or ordinary margarine by a special margarine formulated to that in normal usage the recipient would receive the required amount of the EPA.
This process has not achieved widespread attention, despite the fact that it uses a natural substance which can readily be incorporated into the daily diet. One reason may be due to the difficulty of efficiently separating EPA from natural fish oils to obtain a pure product at reasonable cost. Another reason may be that the effects of administration of EPA are not as dramatic as anticipated.
Rubin U.S. Pat. No. 4,526,902 teach the use of EPA and/or DHA in combination with linoleic acid, .gamma.-linolenic acid and/or DHLA to obtain enhanced effects in the treatment of or prophylaxis against thromboembolic conditions. This patent discloses that the acids may be administered in free acid form or in the form of their physiologically acceptable salts, esters or amides.
Prostaglandins are a family of substances showing a wide diversity of biological effects. Prostaglandins of the 1-, 2-, and 3-series, respectively, incorporate one, two, or three double bonds in their basic 20-carbon carboxylic fatty acid structure which incorporates a 5-member cyclopentene ring.
The 1-series of prostaglandins are strong vasodilators, and inhibit cholesterol and collagen biosynthesis, as well as platelet aggregation. On the other hand, the 2-series prostaglandins are known to enhance platelet aggregation, cholesterol, and collagen biosynthesis, and also to enhance endothelial cell proliferation. The main effect of the 3-series prostaglandins, particularly PGE.sub.3, is the suppression of the 2-series prostaglandins.
The precursor of the 2-series prostaglandins is arachidonic acid ((all-Z)-5,8,11,14-eicosatetraenoic acid). Dihomo-.gamma.-linolenic acid (DHLA) is the precursor for the 1-series prostaglandins, and, as indicated hereinabove, EPA and DHA are precursors for the 3-series prostaglandins.
It is believed that EPA and DHA are effective precursors for prostaglandin PGE.sub.3, which suppresses the 2-series prostaglandins. Additionally, EPA and/or DHA itself competes with arachidonic acid on the same enzymatic system and thus inhibits the biosynthesis of 2-series prostaglandins. This inhibition of the 2-series prostaglandins results in an increase of the ratio of PGE.sub.1 :PGE.sub.2.
It is believed that in rheumatoid arthritis, there are evidences of extremely low levels of PGE.sub.1 and high levels of PGE.sub.2. Further, the anti-inflammatory effect of corticosteroids and the pain killing effect of aspirin are believed to be due to their suppression of PGE.sub.2 formation.
It has recently been discovered that substances in fish oils are effective in treating arthritis in animals. It is believed that the EPA and/or DHA present in the fish oils is the effective agent in fish oil.
Leslie et al., in J. Exp. Med. 1985, 162 1336-1349, disclose that dietary fish oil can be used to decrease the susceptibility to arthritis in mice. However, the fish oil was administered in the unhydrolyzed state.
Prickett et al., in J. Immun. 1984, 725-729, disclose that a fish oil diet, enriched in highly unsaturated long chain fatty acids, provided an increased incidence of collagen-induced arthritis in rats as compared with rats receiving a diet containing beef tallow containing less than 0.05% EPA.
Kremer et al., in Lancet Jan. 26, 1985, 184-187, disclose that the manipulation of fatty acids in the diet can be beneficial in treating arthritis in animals. In this case, the fatty acids were supplemented with EPA from Max-EPA capsules, which contain unhydrolyzed fish oil EPA.
Kremer et al. in Ann. Int. Med. 1987, 106 (4), 497-503, disclose that fish-oil dietary supplements were effective in subjective alleviating active rheumatoid arthritis and reducing neutrophil leukotriene B4 production.